Among the bis-triazole compounds, fluconazole, ie. 2-(2,4-difluorophenyl)-1,3-bis-(1H-1,2,4triazol-1-yl)-propan-2-ol has antifungal activity.
Fluconazole has been prepared by three methods:
In Canadian Patent 1,181,076 a Friedel-Crafts acylation of 1,3difluorobenzene with chloroacetyl chloride results in the formation of 2,4difluoro-.varies.-chloroacetophenone which is then reacted with 1,2,4-triazole to afford 2.4difluoro-.varies.-(1H-1,2,4-triazol-1-yl)acetophenone. The resulting ketone is subjected to a Corey-Chugaev reaction with trimethyl sulfoxonium iodide to form 2-(2,4difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane. Condensation of the resulting epoxide with 1,2,4-triazole affords fluconazole. The overall yield is between 4-8% (Scheme 1).
The preparation can be depicted in the following scheme: ##STR2##
In Canadian Patent 1,181,076, 1-iodo- or 1-bromo-2,4-difluorobenzene is converted to its Grignard or lithiated organometallic complex which is then reacted with 1,3-dichloroacetone to afford 1,3-dichloro-2-(2,4difluorophenyl)-2-propanol. The resulting chlorohydrine is then reacted with two moles of 1,2,4-triazole to afford fluconazole. The last transformation involves the formation of 2-2,4-difluorophenyl)-3-(1H-1,2,4triazol-1-yl)-1,2-epoxypropane as an intermediate as seen in scheme 1.
The process is illustrated in the following scheme: ##STR3##
In Canadian Patent 1,182,822. 1,3-dichloroacetone is reacted with two moles of 1,2,4triazole to afford 1,3di(triazolylacetone). The resulting ketone undergoes a Grignard reaction to lead to fluconazole, as depicted in the following scheme: ##STR4##
In the present application, there is disclosed a process which involves the epoxidation of triazol-containing olefins, followed by reduction of the epoxide obtained to afford fluconazole. The present process offers numerous advantages over the existing art.
First, it allows the obtention of the bis-triazole compounds and specifically fluconazole in considerably higher yields than the existing procedures.
Second, the process is easy to scale up, avoiding the use of a Grignard reaction and a Corey-Chugaev reaction which are extremely air and moisture sensitive and therefore difficult to carry out in large scale.
Third, it does not entail the use of ethers which are extreme fire hazards.
Forth, it results in avoiding the use of highly toxic and corrosive substances such as dichloroacetone and chloroacetyl chloride.
Fifth, the process allows for the formation of a series of unknown epoxide analogues of fluconazole with potential therapeutic value.
Therefore, one object of the present invention is to provide a convenient novel process for the production of bis-triazole derivatives and specifically fluconazole.
It is a further object of the invention to produce new intermediates useful in the manufacture of such bis-triazole compounds. The resulting intermediates are obtained in high yields.